How did antibiotics become part of the food chain?

It all began in 1948 when a biochemist found chickens fed a new antibiotic were growing faster than those without.

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On Christmas Day in 1948, a biochemist named Thomas H. Jukes slipped away from his family and made the short drive to his workplace at drug company Lederle Laboratories in Pearl River, New York. A small experiment with chickens was in progress, and the subordinate who would normally have weighed and fed the birds was home for the holiday.

As he made his rounds, Jukes noticed something peculiar. In one group of a dozen chicks, the feed was being supplemented with a pricey new liver extract, which was certain to make those birds gain weight much faster than normal. But Jukes was puzzled that birds in another group were growing even faster. The only thing added to their feed was a new antibiotic called Aureomycin. “The record shows,” Jukes later wrote, staking his claim to the discovery, “that I weighed the chicks on Christmas Day, 1948.”

No one understood how or why an inexpensive antibiotic could cause animals to put on meat more rapidly. (Even now, researchers talk only about “proposed possible mechanisms” to explain it.) But after some quick follow-up work in the field confirmed the finding, Lederle rolled out its product. It was the beginning of a vast uncontrolled experiment to transform the biology of the animals we eat – and perhaps also the biology of the humans who eat them. Antibiotics added to feed at very small, or subtherapeutic, levels would quickly become a standard tool for rearing food animals, so much so that, even now, about 80% of antibiotic sales in the US go to livestock production rather than to human health care.

The food industry has long argued that any limit on use of antibiotics in livestock feed would be an agricultural disaster, or at least the end of affordable meat. But critics are applying increasing pressure on the industry to address its share of the blame for an epidemic of antibiotic-resistant infections that kills hundreds of thousands of people worldwide each year. So how did antibiotics get into our food supply in the first place? It was largely the work of one otherwise highly esteemed researcher, as well as a classic case of economic interests distorting scientific judgment.

The man who turned antibiotics into animal feed was a remarkablebiologist and an old school environmentalist.

Thomas H. Jukes, the man who turned antibiotics into animal feed, was a remarkable biologist. Born in 1903, he was an old school environmentalist, a life member of the Sierra Club, an enthusiastic outdoorsman, and in later years when he was a professor at the University of California at Berkeley, a pioneer in the new science of molecular biology.

He was also an ardent defender of science, or at least his view of it. He wrote hundreds of opinion pieces, often polemical, on topics of the day, and, among other achievements, fought effectively to prevent the introduction of creationism into California schools. He also campaigned against quack cancer cures, and lambasted Nobel-winning chemist Linus Pauling for advocating massive vitamin doses as a panacea.

Thomas Jukes, formed his ideas in an age of medical miracles, and firmly believed in the power of science to conquer sickness and hunger. – UC Berkeley

But Jukes formed his ideas in an age of medical miracles, and firmly believed in the power of science to conquer sickness and hunger. So he also defended the use of DDT against malaria, even calling attempts to ban the insecticide “unquestionably genocidal”. When the prescription drug DES, or diethylstilbestrol, became notorious in the 1970s for causing birth defects and cancers in young women, Jukes argued for its continued use as a growth promoter in cattle, saying the risk to consumers was minuscule. He took what he saw as a rigorous, evidence-based approach to such questions, in contrast to the supposedly “emotional” language of the emerging environmental movement. He often quoted Renaissance medical writer Paracelsus who believed that everything and nothing is poisonous, or as Jukes noted: “The dose alone makes the poison.”

His fierce opposition to environmental critics undoubtedly reflected his own career history. Before moving to Berkeley in 1963, Jukes had spent his most productive years, from his mid-30s to his late 50s, in the pharmaceutical industry. He worked for Lederle, a division of American Cyanamid, at a facility just outside New York City that now belongs, by a series of mergers, to pharmaceutical giant Pfizer. There, his own writing indicates, he was considerably less rigorous about insisting on detailed experimental evidence.

In particular, his 1985 memoir of how antibiotics first came to be used in livestock feed is often startling to a modern reader because of the casual and freewheeling nature of the pharmaceutical business in the era before the thalidomide birth defect headlines of the 1960s launched strict modern regulation of drug safety. Jukes’ article made it clear that he regarded the unfettered environment in the industry in the mid-20th century as a key to that era’s genius for invention. He and other pioneers “retain a warm spot for those early days”, he wrote.

The introduction of penicillin during World War II was the great world-changing product of that genius, and it prevented tens of thousands of deaths from infected wounds among Allied troops. After the war, the astonishing promise of the antibiotic era set off a scramble for other bacteria-killing drugs. Benjamin Duggar, a botanist who worked mainly on plant diseases caused by fungi, had joined Lederle as a full-time consultant after reaching mandatory retirement age at the University of Wisconsin. Duggar was soon assigned to the search for new antibiotics, which were now making their mark as wonder drugs in civilian health care, too. Duggar’s long interest in fungi soon paid off. “It was a few months later,” Jukes recalled, “that he wrote me that they were having good results, so much so that his assistants and others were ‘stealing’ portions of the crude extracts to cure their colds.” (The idea then was that antibiotics could cure anything, even perhaps cancer.)

Benjamin Duggar, a botanist who worked mainly on plant diseases caused by fungi, was assigned by Lederle to the search for new antibiotics. – Bettmann/CORBIS

Duggar was working with a bacterial species he had collected from the soil at an experimental agronomy plot belonging to the University of Missouri in Columbus. In culture, the bacterium not only demonstrated powerful antibiotic effects, but also produced a yellow pigment for which Duggar named it Streptomyces auriofaciens, or “the gold-bearing streptomyces”.

The name had an apt double meaning. When the president of the company showed off a vial of the stuff to his research committee, he boasted that it “would make a million dollars for Lederle”. This would turn out to be a wild underestimate. By the end of 1948, the antibiotic was being marketed as Aureomycin. It was the first of the tetracycline antibiotics, a genuine miracle drug, effective against a much broader spectrum of disease-causing microbes than the other leading antibiotics, penicillin and streptomycin. Doctors found it particularly useful, The New York Times soon reported, against whooping cough, Rocky Mountain spotted fever, eye infections, typhus, amoebic dysentery, and both streptococcus and staphylococcus infections.

That December, Jukes received a sample to test on chickens. The poultry industry had lately begun to feed its birds soybean meal as a cheaper substitute for fishmeal. But the chickens weren’t thriving. Soybeans lacked an essential ingredient, the elusive “animal protein factor” or “anti-pernicious anaemia factor” that we now know to be the essential vitamin B12. In humans, pernicious anaemia had until recently been routinely fatal; it had killed Alexander Graham Bell, Annie Oakley, and Madame Curie, among many others. Then, in the 1920s, researchers found a lifesaving cure in the form of raw liver. But eating a half-pound of raw liver daily was almost worse than the disease.

A concentrated liver extract became available in the 1940s. Soon after, competing researchers at Glaxo in England and Merck in Rahway, New Jersey, finally identified the life-saving ingredient. The animal protein factor thereafter became known as vitamin B12. Merck didn’t say so at the time, but it had managed to extract B12 from the bacterium Streptomyces griseus, meaning that it could now mass-produce the precious “animal protein factor” in huge fermentation vats.

The New York Times broke the news of the discovery, with the reporter noting that ‘No undesirable side effects have been observed’. – New York Times

Lederle must have felt the competitive pressure. It was also searching for a microbial source of animal protein factor, Jukes later wrote, because researchers there had independently concluded that it was a product not just of animal meat, as the name suggested, but also of microorganisms in an animal’s gut, since it was present in their manure. Jukes and a colleague, Robert Stokstad, were experimenting with hens given just enough feed to allow their eggs to hatch. The resulting “depleted” chicks were generally doomed to die within two weeks unless they got more of the critical animal protein factor.

It was just about the last time for many decades that human medical need for antibiotics would take priority over livestock and drug industry profits.

Some of the chicks received diets supplemented with animal protein factor, in the form of liver extract, and some received an Aureomycin supplement, on a hunch that the bacterium it came from might also produce the animal protein factor. Soon after their experiments began, though, the researchers realised that they had stumbled upon something unexpected. The chicks being fed the Aureomycin brew were growing even faster than chicks supplemented with animal protein factor alone. It seemed to supply the animal protein factor, plus something extra: “an unidentified growth factor that made the chicks grow more rapidly than did a complete diet”. (University of Wisconsin researchers had in fact demonstrated a similar effect with other antibiotics several years earlier, but without any commercial consequence.)

Looking back almost 35 years later, Jukes wrote, “If such a discovery were made … in 1985, there would be round after round of committee meetings, and plans would be made to cope with various US Food and Drug Administration (FDA) roadblocks. Long-term and short-term toxicity tests would be started. Metabolites and residues would be isolated and identified. Above all, the product would be tested for carcinogenicity. Finally, the FDA would refuse permission to market it.

“None of these things took place in 1949.” Instead, the company informed Jukes that his animal feed lab “could have no more of the product because it was needed for the extraction of the antibiotic for use in human medicine”. It was just about the last time for many decades that human medical need for antibiotics would take priority over livestock and drug industry profits.

Testing a tank of Aureomycin in Lederle Laboratories’ New York facility. – SuperStock/getty

Jukes and his staff soon figured out that the “unidentified growth factor” miraculously spurring chick growth was the antibiotic itself. They also found they could get the same growth-promoting effect by feeding chicks on the waste products from the fermentation vats in which Streptomyces auriofaciens was grown, no doubt because some residue inevitably was left behind.

Lederle allowed Jukes to send out Aureomycin samples for testing at universities and agricultural experimental stations. A University of Florida researcher got “the most spectacular results”, a reported tripling of the growth rate in young pigs. Others reported gains that were far smaller but still significant. The company quickly began selling the product, not waiting to complete toxicity testing or routine assays on animals. It sold by the tanker, and demand was intense, particularly in the Midwestern states, where Aureomycin also cured an epidemic of bloody diarrhoea in pigs. A US Senator from Nebraska was soon complaining that his state wasn’t getting its fair share of this miraculous product. A Minnesota pharmacist is said to have bought it in bulk, repackaged it, and sold it at such a high mark-up that he retired to Florida on the profits.

The drug company hailed its antibiotic as having long-range significancefor the survival of the human race.

Misleadingly, Lederle marketed the product at first as a source of vitamin B12, Jukes wrote, and was thus “able to avoid any registration problems”. When the FDA finally found out a year later that American livestock were being fed large quantities of antibiotics, an official there merely asked “what level of Aureomycin should be authorised for use as an animal feed supplement?”, and the company told him.

The New York Times broke the news on its front page on April 10, 1950, under the headline, “'Wonder Drug’ Aureomycin Found to Spur Growth 50%”. Science writer William L. Laurence quoted a Lederle report saying that this “spectacular” discovery held “enormous long-range significance for the survival of the human race in a world of dwindling resources and expanding populations”. The article concluded, “No undesirable side effects have been observed.”

Other studies in that era suggested that adding antibiotics to animal feed could produce a gain in the four to 12% range (and much less in more recent studies, see box), not 50%. But that still represented a significant advantage in the business of getting more meat to market less expensively. By eliminating certain chronic diseases, the daily antibiotic regimen also made it possible to raise animals in highly concentrated facilities. It would become the central feature of modern industrial agriculture. The innovation by Jukes and his colleagues soon spread worldwide, and the era of antibiotics devoted primarily to meat production, rather than to human health, had begun.

The array of pathogens now resistant to the world’s ‘wonder drugs’ is growing, including the multi-drug resistant Staphylococcus aureus shown here. – Scientifica/RMF/Visuals Unlimited/Corbis

Twelve years later, in June of 1962, Rachel Carson’s Silent Spring began to appear in weekly instalments in TheNew Yorker, attacking the uncontrolled use of DDT and other pesticides, and raising broader questions about blind reliance on technological solutions. Jukes promptly responded in Chemical Week with a portrait of a more natural world, in which women had no time to be “writers of science fiction horror stories” because they were too busy “squashing black beetles; beating the clothes moths out of the winter woollens; scraping the mould from the fatback pork; and wondering if they could afford the luxury of a chicken for their Sunday dinner”.

That last line hints that he foresaw the eventual attack on the use of antibiotics as growth promoters in livestock. It came just three years later, when a salmonella strain that was resistant to multiple antibiotics killed six people in the UK. The British government’s “Swann Report” subsequently concluded that the disease organisms “acquired their resistance through the use of antibiotics in animals”. Jukes responded that this remained to be proven. He seemed worried mainly that the press would now “threaten us with the propaganda device of a new Silent Spring”.

When Jukes died in 1999, his friends and colleagues remembered him as a brilliant scientist and polemicist (“cantankerous” but “usually right and always honest”). They also celebrated a decent, well-rounded man, who loved to take his family on hikes into the mountains, was a careful reader of the novels of Aldous Huxley, listened to Bach and Beethoven, could quote Shakespeare at will, held season tickets to Berkeley’s “Cal Bear” football games, and, although he had grown up in England, enjoyed few things more than watching Oakland A’s pitcher Dennis Eckersley strike out the other side in the ninth inning of a close game.

An obituary described Jukes as “one of the giants of 20th century biological science”. He may also have been one of its greatest failures. During the long fight over antibiotics in livestock feed, he always focused on the benefits and minimised the risks. When another deadly outbreak of antibiotic resistant salmonella occurred in 1983, for instance, he noted in Science that “feeding antibiotics to animals has increased meat production by millions of pounds annually for 30 years”. That was what mattered — feeding a hungry world.

Elsewhere, Jukes often stated that he and his fellow researchers at Lederle had always foreseen the danger that feeding antibiotics to livestock would make bacterial strains resistant to antibiotics. But he also discounted the idea that antibiotic resistance would spill over to affect human health. Resistance would occur within the guts of animals receiving the antibiotics, and that mattered to him, he suggested around the time of the Swann Report, mainly on the narrow, practical grounds of “whether the effect of antibiotics on improving growth … in farm animals would disappear in a year or two because of the emergence of resistance. If this were the case, we would indeed be doing more harm than good by temporarily alleviating a problem only to replace it with a more intractable one”. Then he added this chilling sentence: “The experiment to provide the answer was under way on a gigantic scale by 1951 and is still in progress.”

Researchers continue to argue today about the consequences of this willy-nilly global experiment, particularly as the medical world’s “wonder drug” antibiotics become ineffective against an array of virulent pathogens, notably including salmonella, E. coli, MRSA (methicillin-resistant Staphylococcus aureus) and a totally drug-resistant variety of tuberculosis. Margaret Chan, director general of the World Health Organization, warned in 2012 that we stand on the brink of a “post-antibiotic era”. That could mean “an end to modern medicine as we know it. Things as common as strep throat or a child’s scratched knee could once again kill”. Infections caused by resistant strains of E. coli already kill more than 800,000 people each year worldwide. In response to this development, the EU, for example, has banned antibiotic-laced animal feed for boosting growth.

The livestock industry continues to deny that antibiotics in animal feed bear much blame for the growing threat from drug-resistant pathogens. But evidence increasingly indicates that resistance routinely spills over from food animals to people, in ways we are only beginning to recognise. In one revealing study published in 2010, for instance, Public Health Agency of Canada researcher Lucie Dutil and her colleagues monitored the effects when the poultry industry in Quebec briefly suspended use of a standard antibiotic. Levels of resistant salmonella and E. coli on supermarket chicken promptly dropped, as did resistant salmonella infections in humans. When use of the antibiotic resumed, resistant bacteria soon reappeared in both meat products and in human consumers.

Other studies have also found strong circumstantial evidence of a link to antibiotic resistance in humans. If he were alive today, Jukes might still deny that turning antibiotics into animal feed had anything to do with this problem. But given his public record, the remarkable thing is that he encouraged the pharmaceutical industry’s “gigantic” experiment to go forward in the first place. In arguing with his critics, he always insisted that they back up their words with hard scientific evidence. But in his own work at Lederle, with his tantalising new discovery ready to go to market la rgely untested, Jukes had behaved as if all the rules of basic science somehow did not apply. It was an extraordinary act of hubris. And, if those who oppose the practice of feeding antibiotics to livestock are correct, the terrible consequence is that vast numbers of people now pay for it every year with their lives.

What does the data say?

Industry and regulators are only now looking into long-term effects

A USDA study has found growth gains in nursery pigs are not matched in older animals close to market size. – Joe Munroe/getty

Neither industry nor regulators ever conducted a proper large-scale long-term study to test whether the growth promotion Thomas H. Jukes reported was a lasting effect. Even 60 years later, researchers are only beginning to make up for this remarkable omission.

In 2007, researchers at Johns Hopkins University analysed industry data and found that, while antibiotics produced a slight weight gain in chickens, the cost exceeded the resulting commercial benefit. A 2010 study by the US Department of Agriculture likewise found “no statistically significant impact on production” in broiler chickens, and another USDA study in 2011 found significant gains in nursery pigs, but none in animals close to market size.

Data from Denmark and Sweden, where the use of antibiotics in food animals is restricted, clearly show that tight control of the practice “does not lead to long-term negative effects on industry”, says Tyler Smith, a researcher at The Johns Hopkins Center for a Livable Future. “We are squandering a medical miracle on the basis of very limited evidence that it is necessary to produce animals,” he says.

If antibiotics do boost weight gain, even temporarily, how might it happen? Do they inhibit “bad” bacteria that would otherwise impair growth? Do they slow microbial metabolism, freeing up more nutrients for the host animal? Do they thin the intestinal walls or otherwise make it easier for the animal to absorb nutrients? Nobody knows for sure.

One promising development for livestock producers and health advocates alike is that new genetic insights into an animal’s “microbiome” – the microbes that colonise its gut and other niches – may provide far more exact answers to these questions. Livestock producers are already testing beneficial bacteria and other mechanisms to tweak the bacterial processes in an animal’s gut. In one case, using “good” bacteria to crowd out “bad” ones, a strategy called competitive exclusion, reduced the salmonella load in factory-reared turkeys by 90%. That kind of precise control could soon render subtherapeutic antibiotics in animal feed irrelevant.